The discovery of abundant membrane contact sites (MCSs) between the ER and other membrane compartments has revealed that the ER, in addition to its biosynthetic and secretory functions, plays key roles in regulation of organelle dynamics and functions.
We have identified a novel MCS mechanism, where lysosomes make contact with the ER to refuel microtubule motors for transport to the cell membrane (1). Here the lysosomes fuse with the cell membrane to form cellular protrusions. The main regulator of this pathway is the ER-protein Protrudin. When this mechanism is hyper-activated, we find that it promotes cancer development in several ways; by facilitating anabolic mTORC1 signaling (2), cell migration and angiogenesis (3) as well as cancer cell invasion through the formation of invasive protrusions (4). In line with this, high expression of Protrudin in tumors correlates with low survival in several cancer types.
There are additional cancer related processes, like efferocytocis (removal of apoptotic bodies in the tumor) and exosome release that depend on lysosome translocation to the cell surface. We will investigate whether our MCS pathway is involved, and how we can target a hyperactive MCS pathway in cells to prevent tumor growth and invasion.